3. Multidrug resistance in animals

Antimicrobial Resistance Global Report on surveillance [62], issued in 2014 by WHO warned, based on surveillance data recorded, on the major problem represented by antibiotic resistance in a "postantibiotic era. "This definition underlined that most antibiotics, while considered a panacea, were broadly misused in both humans and food-producing animals, thus leading for widespread MDR. In parallel with the discovery of new antibacterial classes of compounds, the induction of resistance was followed closely by the drugs selecting the most resistant of the pathogens, which further spread [62].

One of the less regarded, yet significant sectors in spreading MDR, is represented by the animal segment, and little is known about the epidemiology of MDR in food animals and lesser in wildlife. Similarly to human medicine, veterinary antibiotics in use fail to control not only infections related to conventional agents but are also ubiquitous and commensal bacteria turned into aggressive pathogens. Not only antimicrobial use to control medical situations, such as herd- or flock-based infections (pneumonia, neonatal infections and infections occurring in immune-suppressed animals, surgeries, etc.) [62], but also the use of antimicrobials as growth enhancers in food-producing farmed species (poultry, swine, and cattle) increased the risk represented by animals in spreading MDR. Morbidity and mortality caused by bacteria resistant to commonly used and available for veterinary antibiotics are not the single causes for economic losses in farmed animals. Supplementary cost must be added for food control for antibiotic residues and resistant bacteria in food and disposal of contaminated items. There are many researches on the use of quantitatively active antimicrobial ingredients in farmed animals, showing the amount far exceeds that used in humans.

Enterobacteriaceae represent a large bacteria family, including numerous genera inhabiting human and animal gut of which some synthesize endotoxins. The best known representatives, E. coli and a broad variety of Salmonella spp., were subject to abundant studies. Not only these, but also some other representatives of the family show MDR and also resistance to antibiotics such as last-generation beta-lactams (i.e., carbapenem) used to treat severe bacterial infections and considered to be "the last line of antibiotic defense." A smaller group of carbapenemresistant Enterobacteriaceae (CRE) proved to be carbapenem-nonsusceptible and extendedspectrum cephalosporin resistant, and include Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae complex, Klebsiella pneumoniae, or Klebsiella oxytoca [63]. These species are also found in animals: the Enterobacter complex as commensal microflora in the intestinal tracts of mammals and fish and also pathogenic for insects [64], E. coli in swine, dairy cows' mastitis [65, 66], Klebsiella oxytoca not only in bovine mastitis [67], but also in pets [68].

Multiple antibiotic-resistant bacteria emerging in dairy cows' mastitis as a result of extensive/ uncontrolled drug use, biased therapy, horizontal gene transfer, and/or spontaneous genetic mutations pose an increased health risk to humans by contaminating milk and milk products. Virulence genes in connection with antimicrobial define pathogenic, but also certain commensal strains of E. coli, emphasizing the risks of fecal contamination of animal-derived, including milk products, as an important source for human outbreaks. Furthermore, the severeness of illness is increased in E. coli by the association of MDR with Shiga-like toxin (stx1 and stx2) genes' presence. For example, resistance toward several active substances from commercial products recommended for bovine pathologies: penicillin-streptomycin, tetracycline, neomycin, ampicillin, and amoxicillin/clavulanic acid was found to different extents (MAR 0.2–0.80) —was found in 125 isolates sampled from healthy dairy cows. Multidrug-resistant phenotypes (resistance to more than four antimicrobials) were recorded for 12 isolates (9.6%). The molecular analysis pointed out the presence of stx1 gene in case of 20 strains and stx2 for 11 strains, respectively. The presence of Shiga-like toxin genes (stx1 and stx2) and high MAR index highlight the risk associated with human exposure in terms of possible contamination of milk and dairy products provided by the bovine farms. These results support compulsory food hygiene and safety measures throughout the production chain, to minimize or eliminate the contamination risk for the products provided by these farms [Crisan et al., unpublished data, 2018].

be representative for the general population of dogs, a special canine category was investigated in this regard—the case of dogs that participate in animal-assisted interventions (AAIs), also named "therapy dogs": since these animals commonly interact with immunocompro-

Antimicrobial Resistance Global Report on surveillance [62], issued in 2014 by WHO warned, based on surveillance data recorded, on the major problem represented by antibiotic resistance in a "postantibiotic era. "This definition underlined that most antibiotics, while considered a panacea, were broadly misused in both humans and food-producing animals, thus leading for widespread MDR. In parallel with the discovery of new antibacterial classes of compounds, the induction of resistance was followed closely by the drugs selecting the most resistant of the

One of the less regarded, yet significant sectors in spreading MDR, is represented by the animal segment, and little is known about the epidemiology of MDR in food animals and lesser in wildlife. Similarly to human medicine, veterinary antibiotics in use fail to control not only infections related to conventional agents but are also ubiquitous and commensal bacteria turned into aggressive pathogens. Not only antimicrobial use to control medical situations, such as herd- or flock-based infections (pneumonia, neonatal infections and infections occurring in immune-suppressed animals, surgeries, etc.) [62], but also the use of antimicrobials as growth enhancers in food-producing farmed species (poultry, swine, and cattle) increased the risk represented by animals in spreading MDR. Morbidity and mortality caused by bacteria resistant to commonly used and available for veterinary antibiotics are not the single causes for economic losses in farmed animals. Supplementary cost must be added for food control for antibiotic residues and resistant bacteria in food and disposal of contaminated items. There are many researches on the use of quantitatively active antimicrobial ingredients in farmed ani-

Enterobacteriaceae represent a large bacteria family, including numerous genera inhabiting human and animal gut of which some synthesize endotoxins. The best known representatives, E. coli and a broad variety of Salmonella spp., were subject to abundant studies. Not only these, but also some other representatives of the family show MDR and also resistance to antibiotics such as last-generation beta-lactams (i.e., carbapenem) used to treat severe bacterial infections and considered to be "the last line of antibiotic defense." A smaller group of carbapenemresistant Enterobacteriaceae (CRE) proved to be carbapenem-nonsusceptible and extendedspectrum cephalosporin resistant, and include Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae complex, Klebsiella pneumoniae, or Klebsiella oxytoca [63]. These species are also found in animals: the Enterobacter complex as commensal microflora in the intestinal tracts of mammals and fish and also pathogenic for insects [64], E. coli in swine, dairy cows' mastitis

[65, 66], Klebsiella oxytoca not only in bovine mastitis [67], but also in pets [68].

mised people, the risks cannot be minimized [54, 56, 57, 61].

mals, showing the amount far exceeds that used in humans.

3. Multidrug resistance in animals

98 Antimicrobial Resistance - A Global Threat

pathogens, which further spread [62].

A study conducted in Canada by Finley et al. [56] indicated for commercially available canine raw food diets, an overall Salmonella prevalence of 21%, with chicken as an ingredient for 67% of the Salmonella-positive diets. Eighteen distinct serotypes displaying resistance toward 12 of the 16 antimicrobials tested, and a predominant pattern of ampicillin and tetracycline resistance entitled the authors to conclude on the need for implementing regulatory guidelines for the production of these diets aimed to reduce or to eliminate the associated risks for pets and the contact people.

Also, outbreaks of human salmonellosis related to exposure to animal-derived pet treats (pig ear, beef steak patty dog, and pet treats of seafood origin) have been reported in Canada, with the laboratory confirmation of Salmonella contamination in case of mentioned pet treats and identification of the following serotypes: S. Bovismorbificans, S. Give, S. Derby, and S. Typhimurium var. Copenhagen. The overall prevalence of 4% was regarded as lower compared to data reported in 1999, but the isolates showed resistance to up to seven antimicrobials [56]. A significant higher prevalence with 41% (65/158) of samples found positive for Salmonella was reported in case of dog treats derived from pig ears and other animal parts randomly collected in USA [28].

Updates on the antimicrobial resistance trends are needed in order to select the most suitable choices for the antibacterial therapy particularly in case of methicillin-resistant Staphylococcus aureus (MRSA) infections. Regarded as an opportunist organism, MRSA is responsible not only for localized skin and soft-tissue infections, but also for invasive forms such as septicemia and toxic shock syndrome [45]. Severe clinical outcomes and added costs justify further research for alternative treatments.

Due to the high diversity of MDR bacteria isolated from numerous animal sources and food of animal origin, an integrated meta-analysis of data could support the upgraded short-, medium-, and long-term strategies to control antimicrobial resistance and its further development, which in their turn are important for preventing the emergence and cross-country/ continent spreading of resistant strains [69].

4.1. Plant extracts acting against bacteria indirectly: immunological uses

of medications exclusively of flowering plant origin [71].

acquired resistance of the body to infections [17, 18, 72].

4.2. Direct antibacterial activity of plant extracts

on the in vitro bacteriostatic/bactericidal effects.

individuals with induced or innate immunosuppression [77–82].

Current trends in medicine tend to include natural products in therapy, without mixing allopathic and homeopathic treatments, the latest gaining more and more in comparison with chemically obtained compounds. The WHO list of 252 basic and essential drugs includes 11%

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Vegetal extracts from various plant origins are used more and more, with a favorable activity in diminishing the negative impact of numerous microbial agents or in improving the innate or

Classical therapeutic protocols supplemented with vegetal extracts could increase the protective capacity of the individuals, by their complex action mechanisms, which stimulate immunity. This pattern is actually applied in veterinary medicine, where certain stress-induced changes, caused by intensive raising/farming of food species, could be corrected in this manner [73–76]. Moreover, active principles proved to be potent in restoring the immune reactivity in

Vaccines against bacterial diseases represent one of the most powerful tools for prevention and control. Within this framework, researches on the immune stimulating activities of vegetal extractions were successful, with obvious immune modulating effects. Due to improved bioavailability as compared to conventional drugs, combined with immune modulating potential, the question on plant extracts as potential adjuvants emerged for vaccines broadly used to prevent infectious diseases, in both humans and animals. An appropriate understanding of adjuvant potential of vegetal extracts and experimental design to investigate these possibilities

would lean on a good knowledge of general action mechanisms of vaccine adjuvants.

Antimicrobial effects of plant extracts on clinical isolates from farmed and pet animals and their potential use to improve health and lower the risk for humans were illustrated by experiments aiming to investigate the influence of the plant taxonomy/chemical composition

Plant extracts were initially proposed as supplementary means in combined antibiotic and natural therapies; therefore, the synergism between plant extracts and antibiotics was also observed in experimental studies. In a complex research carried out to establish the antimicrobial effect of certain plants: Achillea millefolium (yarrow), Caryophyllus aromaticus (clove), Melissa officinalis (lemon-balm), Ocimum basilicum (basil), Psidium guajava (guava), Punica granatum (pomegranate), Rosmarinus officinalis (rosemary), Salvia officinalis (sage), Syzygium jambolanum (jambolan), and Thymus vulgaris (thyme) on bacteria resistant from 1 to 18 antibiotics: amikacin, ampicillin, cephalothin, cefpirome, carbenicillin, cefoxitin, chloramphenicol, ceftriaxone, cefotaxime, erythromycin, gentamicin, kanamycin, lincomycin, methicillin, nalidixic acid, netilmicin, norfloxacin, nitrofurantoin, penicillin, piperacillin, rifampicin, sulfonamide, sulfamethoxazole, tobramycin, tetracycline, vancomycin (Proteus spp., Klebsiella pneumoniae, Shigella spp., Pseudomonas aeruginosa,
